Septic shock is an often fatal condition that results from severe infections, most often caused by Gram-negative bacteria including Escherichia coli, Pseudomonas aeruginosa and Klebsiella and Bacteroides species. Gram-positive bacterial infections can also lead to septic shock, particularly those caused by Staphylococcus aureus and the Pneumococci. The bacterial infections can be acquired via the usual routes-ingestion of contaminated food or water-but can also result as a consequence of surgical procedures including catherization and implantation of prosthetic devices. In addition, patients with depressed immune function-for example, cancer chemotherapy patients-are also susceptible to overwhelming bacterial infections which a patient with a normal immune system could handle easily.
The sequence of events that evolves into septic shock is initiated by the release of large quantities of a bacterial endotoxin into the blood stream in the case of Gram-negative organisms or of the release of a comparable product-cell wall substances-in the case of Gram-positive bacteria, yeast and fungal infections. The bacterial endotoxin is a component of the bacterial cell wall. The active part of the endotoxin is a lipopolysaccharide (LPS). LPS consists of three parts; an oligosaccharide side chain which varies among bacterial species, and two less variable parts, a core polysaccharide and Lipid A. LPS binds to immunoglobin M and this complex activates the complement system with the release of C3b, which material in turn activates the polymorphonuclear leukocytes (PMN), monocytes, neutrophils, macrophage and endothelial cells. The activation of these substances stimulates the release of several mediators of septic shock including tumor necrosis factor (TNFalpha) interleukin-1 (IL-1) and other interleukins including IL6 and IL-8, platelet-activating factor (PAF), prostaglandins and leukotrienes-see Ann. Intern. Med. 115 464-6 (1991) for a comprehensivelisting. Of the above, the two cytokines TNFalpha and IL-1 lead to many of the physiologic changes which eventuate into septic shock.
The activated PMNs, among other mediators, cause the formation of oxygen-containing free-radicals. These free-radicals are produced as part of the body's defense against the invasion of foreign organisms and their toxic products. PMN specifically generates the superoxide anion radical (*O.sub.2 --). This free-radical when acted upon by the enzyme superoxide dismutase (SOD) forms hydrogen peroxide. Excess hydrogen peroxide in the presence of iron generates a second oxygen-containing free-radical, the hydroxyl free-radical (*OH). In addition, activated neutrophils can generate oxyradicals by stimulating the NADPH oxireductase reaction. The release by neutrophils of both oxyfree-radicals and proteases causes extensive damage to endothelial cells. In addition, adhesion of activated neutrophils to endothelial cells leads to vascular permeability, which in turn causes much of the damage associated with septicemia and septic shock.
The LPS-stimulated macrophages also release other free-radicals, including oxyfree-radicals from arachidonic acid metabolism, which free-radicals can also cause extensive damage to endothelial cells. These damages lead to coagulation deficiencies and circulatory collapse which in turn lead to hypotension, tissue damage, multi-organ failure and death. Thus, excess production of the above mentioned free-radicals is linked to the mortality associated with septic shock.
Current treatment for septicemia includes administration of antibiotic to kill the invading bacteria and infusion of fluids to counter hypotension. Unfortunately, the bacteria killed by the antibiotic can worsen the septicemia by releasing additional quantities of endotoxin and LPS. Other possible therapeutic procedures include use of monoclonal antibodies to bind LPS and products to block the action of cytokines by again using monoclonal antibodies to bind TNFalpha and IL-1.
Another possible treatment method for septicemia would be the use of drugs that would either stop the production of oxyfree-radicals or would act to neutralize such radicals, as by a scavenging action or a free-radical chain reaction terminating action. Of particular importance would be the provision of drugs that that can scavenge the superoxide anion radical and the hydroxyl free-radical. It is thus a further object of this invention to provide free-radical scavengers and compounds capable of terminating free-radical chain reactions in vivo. Since such free-radicals contribute materially to the deleterious physiologic changes which culminate in septic shock, such drugs should help to alleviate the consequence of septicemia and hence avoid the end result of those effects,